Congenital muscular dystrophy with defective alpha-dystroglycan, cerebellar hypoplasia, and epilepsy.

Department of Paediatric Neurology, Catholic University, Rome, Italy.
Neurology (Impact Factor: 8.25). 11/2009; 73(19):1599-601. DOI: 10.1212/WNL.0b013e3181c0d47a
Source: PubMed
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    ABSTRACT: The alpha-dystroglycanopathies are genetically heterogeneous muscular dystrophies that result from hypoglycosylation of alpha-dystroglycan (α-DG). Alpha-dystroglycan is an essential link between the extracellular matrix and the muscle fiber sarcolemma, and proper glycosylation is critical for its ability to bind to ligands in the extracellular matrix. We sought to identify the genetic basis of alpha-dystroglycanopathy in a family wherein the affected individuals presented with congenital muscular dystrophy, brain abnormalities and generalized epilepsy. We performed whole exome sequencing and identified compound heterozygous GMPPB mutations in the affected children. GMPPB is an enzyme in the glycosylation pathway, and GMPPB mutation were recently linked to eight cases of alpha-dystroglycanopathy with a range of symptoms. We identified a novel mutation in GMPPB (p.I219T) as well as a previously published mutation (p.R287Q). Thus, our work further confirms a role for GMPPB defects in alpha-dystroglycanopathy, and suggests that glycosylation may play a role in the neuronal membrane channels or networks involved in the physiology of generalized epilepsy syndromes.
    Brain research 04/2014; · 2.46 Impact Factor
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    ABSTRACT: Congenital muscular dystrophies (CMDs) are early onset disorders of muscle with histological features suggesting a dystrophic process. The congenital muscular dystrophies as a group encompass great clinical and genetic heterogeneity so that achieving an accurate genetic diagnosis has become increasingly challenging, even in the age of next generation sequencing. In this document we review the diagnostic features, differential diagnostic considerations and available diagnostic tools for the various CMD subtypes and provide a systematic guide to the use of these resources for achieving an accurate molecular diagnosis. An International Committee on the Standard of Care for Congenital Muscular Dystrophies composed of experts on various aspects relevant to the CMDs performed a review of the available literature as well as of the unpublished expertise represented by the members of the committee and their contacts. This process was refined by two rounds of online surveys and followed by a three-day meeting at which the conclusions were presented and further refined. The combined consensus summarized in this document allows the physician to recognize the presence of a CMD in a child with weakness based on history, clinical examination, muscle biopsy results, and imaging. It will be helpful in suspecting a specific CMD subtype in order to prioritize testing to arrive at a final genetic diagnosis.
    Neuromuscular Disorders 01/2014; · 3.46 Impact Factor
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    ABSTRACT: Glycans are highly diverse carbohydrate moieties that have been selected in evolution to convey dynamic structural and functional properties to the macromolecules to which they are attached. For this reason, correct glycan synthesis is essential for various developmental and physiological processes, particularly in multicellular organisms that use them as communication pathways. The disruption of glycan synthesis frequently results in multisystemic disease with neurological involvement. Congenital disorders of glycosylation (CDGs) have been and will likely remain a rapidly growing group of genetic human diseases that involve different defects in the synthesis or remodelling of N-and O-linked glycans as well as defects in glycosphingolipid and glycosylphosphatidylinositol (GPI) anchor glycosylation. The molecular and clinical characterization of CDGs has enormously contributed to understanding the physiologic roles of the glycosylation machinery and its interaction with other cellular machineries. More than 50 different types of defects have been described and although the first type was described in 1984, CDGs remain widely under-diagnosed or misdiagnosed. This review describes the genetic and biochemical basis of CDGs, as well as the clinical phenotypes and current methods to diagnose them that are ultimately required to establish corrective treatments that are also discussed.
    05/2012: pages 59-82; , ISBN: 1619425416